Abstract
Abnormalities in G protein-mediated signal transduction could be involved in the pathogenesis of diabetic polyneuropathy (DPN). Here we test whether the GNB3 C825T variant confers susceptibility to DPN in type 1 diabetes (T1D) mellitus. The C825T marker of GNB3 was genotyped in genomic DNA from blood isolated from a total of 213 Russian T1D patients 100 of whom had DPN. Compared to carriers of the wild-type genotypeC/C, diabetic subjects with genotypesT/Thad significantly increased risk to develop DPN (Odds Ratio (OR) of 4.4 (p= 0.001). The adjustment for confounders (age, sex, body mass index, cigarette smoking, and level of reduced glutathione) resulted in increase of the OR value up to 4.72 (p= 8.9 × 10-3). The further adjustment for hypertension abolished the association between the GNB3 C825T variant and DPN (OR = 1.95,p= 0.18). Non-complicated subjects homozygous forT/Tshowed decreased levels of reduced glutathione (T/T: 69 ± 19 vs.C/T: 74 ± 19 vs.C/C: 77 ± 17 μmol/l,p= 0.009). Compared to other GNB3 variants, carriers of theT/Tgenotype had elevated systolic blood pressure (SBP) in complicated (T/T: 115.8 ± 9.1 vs.C/T: 113.3 ± 8.2 vs.C/C: 109.5 ± 8.7 mm/Hg,p= 0.036) and non-complicated T1D patients (T/T: 118.1 ± 8.4 vs.C/T: 116.9 ± 7.9 vs.C/C: 112.1 ± 7.2 mm/Hg,p= 0.02). However, the significance of association between the C825T polymorphism was lost after adjustment for confounding risk factors. In conclusion, the 825T allele of GNB3 is likely to accelerate the development of DPN through primary effects to SBP and hypertension in subgroups of diabetic patients with impaired neurovascular function and advanced oxidative stress.
Highlights
Heterotrimeric guanine nucleotide-binding proteins (G proteins) are expressed in all human cells
We considered the glutathione level, which could reflect the severity of oxidative stress, as well as age, gender, smoking, hypertension, and body mass index (BMI) as potential confounders that could influence interactions between the C825T polymorphism of GNB3 and other variances [18]
We found association between the 825T variant of GNB3 and higher risk of polyneuropathy in Russian type 1 diabetic (T1D) patients
Summary
Heterotrimeric guanine nucleotide-binding proteins (G proteins) are expressed in all human cells. We reported association between the GNB3 C825T variant and neuropathy in type 1 diabetic (T1D) Russian patients. The genotype T /T was significantly associated with increased systolic blood pressure in both DPN patients (CC vs CT vs TT = 109.5 ± 8.7 vs 113.3 ± 8.2 vs 115.8 ± 9.1 mm/Hg, p = 0.036) and individuals with no neuropathy (CC vs CT vs TT = 112.1 ± 7.2 vs 116.9 ± 7.9 vs 118.1 ± 8.4 mm/Hg, p = 0.02).
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